Invest in ME/Prof Jonathan Edwards statement on UK Rituximab trial, 30 July

[Jonathan Edwards]

With from somewere else you mean the retrovirus antibodies they used?

It falls outside this trial but the question is why do patients pDC's in the duodenum make EVR proteins.

Yes, I guess the antibodies were from some lab reagent raised against the virus. I am not sure you can conclude that the cells were making viral proteins. Dendritic cells pick up antibodies in other ways and the antibody reagent may happen to cross react with some human protein. Cross reactivities are very very common when using lab raised antibodies but I am sceptical about them occurring in real human beings.

 

[Legendrew]

Would the improvement some people experience over time and that seen in the Norwegian trials suggest to you an autoimmune attack where the tissue isn't damaged or where the tissue damaged has a reasonably high affinity for repair and cell replication?

I can't help but think that during 6 month duration until improvement, a damaged tissue (whatever it could be) could potentially repair itself in the absence of the autoantibodies. To me the 6 month duration seems too long a period for autoantibody levels dropping to be the only process occurring - i'm not sure how long the improvement takes in other diseases such as RA but i've seen reports of people seeing improvement at 6 weeks following treatment.

 

[heapsreal]

What sort of testing or where should they been looking to know if a patient is going to be a responder to ritux?

I have heard from a couple of people who have negatively responded to ritux who fit the cfs/me diagnosis and have low nk function. I just mention this as there is evidence of cfs/me people having active infections and to me it seems a scary thought to knock out apart of our immune system with ritux.

I have spoken to quite a few people with auto immune illnesses and i ask them if they think their condition was triggered by an infection, many say yes. So is it possible that some may have ongoing infections?

I wonder with cfs/me if there is a sub set who have chronic infections, another group who are auto immune and another who are a mixture. I think that it would be important to sub set people atleast into these 3 groups. Maybe this is the thinking behind Open Medicine wanting to do a trial of ritux and valcyte together??

I just cant help but think its important to treat those active infections in patients before using a treatment like rituximab. I think there is too much evidence showing active infections as well as the improvement many make treating infections which is evidence of active infections. On the other hand there is definately a group of people who dont respond to treating infections and viral titres are ify at best of representing active infections, these people maybe better responders to ritux only treatment.

The above are my thoughts and concerns, would like to hear your opinions on those Prof Ed. Thanks again for contributing to this forum and keeping us informed.

cheers!!!

 

[Jonathan Edwards]

Would the improvement some people experience over time and that seen in the Norwegian trials suggest to you an autoimmune attack where the tissue isn't damaged or where the tissue damaged has a reasonably high affinity for repair and cell replication?

I can't help but think that during 6 month duration until improvement, a damaged tissue (whatever it could be) could potentially repair itself in the absence of the autoantibodies. To me the 6 month duration seems too long a period for autoantibody levels dropping to be the only process occurring - i'm not sure how long the improvement takes in other diseases such as RA but i've seen reports of people seeing improvement at 6 weeks following treatment.

I think if there was structural tissue damage somebody would have found it on an MRI scan or something by now, so I doubt any cell replication would be needed. That to me is good news because it suggests that full recovery ought to be perfectly possible. The only detailed analysis of autoantibody levels over a long period after rituximab that I know of is that done by Jo Cambridge. She has done thousands of assays on rheumatoid and lupus sera. One or two other groups have done more limited studies and the results are pretty similar. In RA it can take at least 6 months for autoantibody levels to drop and in fact there is usually some residual level that goes on for years. In lupus antibodies to antigens like RNP and Sm do not go down much over very long periods - which may be why some features of lupus do not improve so much. So I think the slowness of autoantibody fall is all we need to explain the six month time span. Improvements after rituximab have been reported earlier in some conditions but one has to be careful because steroids are often given as premedication. Immune thrombocytopenia seems to improve quickly and that might have something to do with a very short half life for antibodies that bind platelets or a fall below a threshold of antibodies forming complexes of certain sizes.

 

[Jonathan Edwards]

I have heard from a couple of people who have negatively responded to ritux who fit the cfs/me diagnosis and have low nk function. I just mention this as there is evidence of cfs/me people having active infections and to me it seems a scary thought to knock out apart of our immune system with ritux.

I have spoken to quite a few people with auto immune illnesses and i ask them if they think their condition was triggered by an infection, many say yes. So is it possible that some may have ongoing infections?

I just cant help but think its important to treat those active infections in patients before using a treatment like rituximab. I think there is too much evidence showing active infections as well as the improvement many make treating infections which is evidence of active infections. On the other hand there is definately a group of people who dont respond to treating infections and viral titres are ify at best of representing active infections, these people maybe better responders to ritux only treatment.

We have covered some of this before, I think. I am a bit doubtful about the meaning of NK assays now that we know the complexities of the KIR/KAR receptor systems. It might be worth checking NK assays in patients if we find responder and a non-responder subgroups that links to B cell function. But low NK results on standard K562 assays might actually be part of a B cell related mechanism. My information so far about the literature is that there are no consistent findings of active infections. There may be immune responses (antibody titres) but that may just mean that a distrurbed immune system 'thinks' there is an infection. An awful lot of rituximab has been used and the issue of reactivation of viral infections does not seem to be widespread. Zoster reactivation is probably more common but it settles much in the way it usually does.

 

[MeSci]

In RA it can take at least 6 months for autoantibody levels to drop and in fact there is usually some residual level that goes on for years. In lupus antibodies to antigens like RNP and Sm do not go down much over very long periods - which may be why some features of lupus do not improve so much. So I think the slowness of autoantibody fall is all we need to explain the six month time span. Improvements after rituximab have been reported earlier in some conditions but one has to be careful because steroids are often given as premedication. Immune thrombocytopenia seems to improve quickly and that might have something to do with a very short half life for antibodies that bind platelets or a fall below a threshold of antibodies forming complexes of certain sizes.

Sorry if I've asked this (and you replied!) before, but could the variation in response between different diseases (and maybe individuals with the same diseases) be partly or wholly due to the persistence of mechanisms that created the autoimmunity in the first place?

 

[voner]

We have covered some of this before, I think. I am a bit doubtful about the meaning of NK assays now that we know the complexities of the KIR/KAR receptor systems. It might be worth checking NK assays in patients if we find responder and a non-responder subgroups that links to B cell function. But low NK results on standard K562 assays might actually be part of a B cell related mechanism. My information so far about the literature is that there are no consistent findings of active infections. There may be immune responses (antibody titres) but that may just mean that a distrurbed immune system 'thinks' there is an infection. An awful lot of rituximab has been used and the issue of reactivation of viral infections does not seem to be widespread. Zoster reactivation is probably more common but it settles much in the way it usually does.

Prof. Edwards,

Your last response is really quite stunning and significant to people who participate in this forum. I'm glad you reiterated your statements about NK cell function. You might remember that one of the symptoms of ME/CFS is poor memory function, Thus Some of us forget easily and it's darn hard to search through this entire thread to find information!

Here's what I gleaned from Your above quote:

1. Your statement implies that you don't see really much evidence for active infections to be significant in the determination of your (or anybody's) patient set?

2. You state that NK cell function tests are probably inaccurate and the low NK so function is just a result of B cell issues.

Your statements really seem to be at odds with the Clinical practices of the most experienced and respected clinician/researchers in this field. Although I have not personally experienced going to one of these clinicians, I have read enough to understand that the preeminent clinicians/researchers like Dr. Peterson, Dr. Klimas her clinic, etc. all run pretty extensive immunological panels and check for all sorts of infections be it herpes or enterovirus, etc. Then these clinician spent a lot of time doling out drugs etc. in order to beat down these infections.

I would love to hear your comments on this possible difference of opinion between you and these other preeminent clinician/researchers (Or am I misreading your statements?) So are you saying that all these efforts by these clinicians and us patients looking for and treating infections might all be for naught?

 

[Bob]

voner, research into pathogens has been mixed, at best. I don't think this is a controversial issue. The studies looking at viruses struggle to isolate viruses, and usually find anti-bodies (with mixed results) rather than actual virus. When anti-virals are tested in research trials, the results are also mixed, and not very successful.

The clinicians, who you refer to, do not use a single approach to treatment, but they mix and match, finding out what works best for each patient. My understanding is that they use a battery of tests, which give them clues to treatment, but there's no single treatment that works well for each set of test results.

As for NK cell function, I'm not aware of any research that has changed the field massively, and led to either a biomarker or successful treatment. And I'm not certain if results have been consistent, in terms of looking for biomarkers.

The best research that I'm aware of has been from people like the Lights, who showed that cytokines levels change drastically after exertion. But, again, I'm not sure if the changes are predictable.

That's my understanding anyway, but I might have missed some essential research.

 

[heapsreal]

voner, research into pathogens has been mixed, at best. This is not a controversial issue. The clinicians who you refer to do not use a single approach to treatment, but they mix and match, finding out what works best for each patient. The studies into viruses struggle to isolate viruses, and usually find anti-bodies (with mixed results) rather than actual virus.
When anti-virals are tested, the results are also mixed, and not very successful in clinical trials.

As for NK cell function, I'm not aware of any research that has changed the field massively, and led to either a biomarker or successful treatment. And I'm not certain if results have been consistent, in terms of looking for biomarkers.

The best research that I'm aware of has been from people like the Lights, who showed that cytokines levels change after exertion. But, again, I'm not sure if the changes are predictable.

That's my understanding anyway, but I might have missed some essential research.

bond/griffith uni in australia tested approx 100 cfsers and 50 healthy controls 6 monthly over an 18 month period. the findings were that the cfs group had low nk function as well as low nk bright cell function and cd8 t cell function. when one looks at the role of nk and cd8 cells, then if they are low functioning then its going to leave one open to infections and reactivation of infections. recently the did a study on severe cfsers showing the same results.

I really think there is going to be a subset who's immune system has cleared those triggering infections but for some reason the immune system stays switched on. Then another group who's immune system isnt strong enough to clear these triggering infections as well as leaving them open to other infections??

 

[Legendrew]

bond/griffith uni in australia tested approx 100 cfsers and 50 healthy controls 6 monthly over an 18 month period. the findings were that the cfs group had low nk function as well as low nk bright cell function and cd8 t cell function. when one looks at the role of nk and cd8 cells, then if they are low functioning then its going to leave one open to infections and reactivation of infections. recently the did a study on severe cfsers showing the same results.

I really think there is going to be a subset who's immune system has cleared those triggering infections but for some reason the immune system stays switched on. Then another group who's immune system isnt strong enough to clear these triggering infections as well as leaving them open to other infections??

From my understanding NK cells themselves are a rather general lymphocyte playing a bigger role in innate immunity - the research to me implies that there is something not right in the immune system as a whole but doesn't elude much as to what it might be. Certainly there is research and evidence showing that the NK cells are not functioning as they should, but given their numerous roles it's not the smoking gun some people want it to be - more the distant smell of burning gunpowder.

I have been reading into the topic of Nk cell - B-cell interactions and there is the potential for the NK cells to become somewhat dysregulated if a problem arises in the B-cells and vice versa so perhaps that's what we're seeing. Interesting to see the sheer number of interactions going on between the differing arms of the immune system.

 

[cornwall13]

Professor Edwards

If rituximab works for a subset of patients, but then relapses, but further maintenance doses work, do you think this could be done indefinitely? Or will the rituximab become less effective over time with repeated doses?

Regards

 

[Jonathan Edwards]

Prof. Edwards,

Your last response is really quite stunning and significant to people who participate in this forum. I'm glad you reiterated your statements about NK cell function. You might remember that one of the symptoms of ME/CFS is poor memory function, Thus Some of us forget easily and it's darn hard to search through this entire thread to find information!

Here's what I gleaned from Your above quote:

1. Your statement implies that you don't see really much evidence for active infections to be significant in the determination of your (or anybody's) patient set?

2. You state that NK cell function tests are probably inaccurate and the low NK so function is just a result of B cell issues.

Your statements really seem to be at odds with the Clinical practices of the most experienced and respected clinician/researchers in this field. Although I have not personally experienced going to one of these clinicians, I have read enough to understand that the preeminent clinicians/researchers like Dr. Peterson, Dr. Klimas her clinic, etc. all run pretty extensive immunological panels and check for all sorts of infections be it herpes or enterovirus, etc. Then these clinician spent a lot of time doling out drugs etc. in order to be down these infections.

I would love to hear your comments on this possible difference of opinion between you and these other preeminent clinician/researchers (Or am I misreading your statements?) So are you saying that all these efforts by these clinicians and us patients looking for and treating infections might all be for naught?

That's a tricky one to answer. Maybe I should just say that when I developed rituximab for RA I had a reputation for 'statements at odds with the Clinical practices of the most experienced and respected clinician/researchers in the field'. I thought it was important to be 'at odds' if I was going to get any progress. This time I'm not betting my shirt on anything - everyone else thinks trying rituximab is a good idea - so hopefully I won't end up looking as half dead as I did in 2001 http://www.ucl.ac.uk/profile/successes2.html !

I am not saying that the NK cell assays are inaccurate. The question is exactly what is being measured? I like the idea that there is something unusual about NK cells in ME but I am not sure what it is.

 

[heapsreal]

From my understanding NK cells themselves are a rather general lymphocyte playing a bigger role in innate immunity - the research to me implies that there is something not right in the immune system as a whole but doesn't elude much as to what it might be. Certainly there is research and evidence showing that the NK cells are not functioning as they should, but given their numerous roles it's not the smoking gun some people want it to be - more the distant smell of burning gunpowder.

I get where your coming from but with low nk function we are going to be prone to infections. Im not saying low nk function is the cause, maybe a consequence of something else, but we dont know. But the role of nk cells is to kill cancer cells and viruses. I dont think infections should be ignored.

Maybe more light will be shed on nk cells when griffith uni do studies comparing nk bright and dim cells in cfs/me, RA and MS.

 

[Legendrew]

I get where your coming from but with low nk function we are going to be prone to infections. Im not saying low nk function is the cause, maybe a consequence of something else, but we dont know. But the role of nk cells is to kill cancer cells and viruses. I dont think infections should be ignored.

I don't think infections are being ignored - certainly I feel incredibly ill now when I get an infection, so certainly infections have the potential to be a co-morbid problem especially considering the accounts of immune dysfunction, but given that they've been quite extensively studied in ME/CFS in the past to little avail, it seems apt to give an autoimmune causation a chance. For some, active infections could well be the problem since we're undoubtedly not dealing with one disease, but if there is an autoimmune group, they may be one of the easier groups to separate from everyone else - separating the different diseases and treating them effectively has to be the end target and i'm hopeful this could be the start of this,

 

[Jonathan Edwards]

Sorry if I've asked this (and you replied!) before, but could the variation in response between different diseases (and maybe individuals with the same diseases) be partly or wholly due to the persistence of mechanisms that created the autoimmunity in the first place?

My understanding is that autoimmunity either causes itself, in the sense of random generation of vicious cycling B cells, or is triggered by an error in the early generation of an immune response to a microbe. In the first case variation in response could be due to persistence of the effect of the autoimmunity - in terms of long lived plasma cells producing antibodies. In the second I doubt persistence of a microbe would make much difference once the mistake was made. I could be wrong.

 

[Jonathan Edwards]

Professor Edwards

If rituximab works for a subset of patients, but then relapses, but further maintenance doses work, do you think this could be done indefinitely? Or will the rituximab become less effective over time with repeated doses?

Regards

Good question. The evidence we have so far is that you can go on using rituximab for up to fifteen years in a good proportion of patients with autoimmunity without loss of efficacy. In fact the main problem is a gradual drop in protective antibody levels. Nobody is sure if that is important but we tend to stop using the drug if it happens. I actually see rituximab as a stop gap in all this. My hope would be that in ten years time there will be easier B cell targeted drugs to use - with long term relief.

 

[Legendrew]

Good question. The evidence we have so far is that you can go on using rituximab for up to fifteen years in a good proportion of patients with autoimmunity without loss of efficacy. In fact the main problem is a gradual drop in protective antibody levels. Nobody is sure if that is important but we tend to stop using the drug if it happens. I actually see rituximab as a stop gap in all this. My hope would be that in ten years time there will be easier B cell targeted drugs to use - with long term relief.

Would it have to be anti B-cell therapy? I've been thinking recently and read a little into anti-antibodies which have some potential. Being proteins, antibodies themselves have the potential to be bound to and have a highly specific region built into their structure. I realise we're a long way off being able to construct and manufacture such an antibody but it could theoretically work. The only problem I could thing of would be other things binding to it which could be problematic.

I suppose through anti-B cell therapies you're eliminating the cause of the problem but it does come with the obvious risks of immuno-suppression.

http://www.ncbi.nlm.nih.gov/pubmed/79255

 

[voner]

That's a tricky one to answer. Maybe I should just say that when I developed rituximab for RA I had a reputation for 'statements at odds with the Clinical practices of the most experienced and respected clinician/researchers in the field'. I thought it was important to be 'at odds' if I was going to get any progress. This time I'm not betting my shirt on anything - everyone else thinks trying rituximab is a good idea - so hopefully I won't end up looking as half dead as I did in 2001 http://www.ucl.ac.uk/profile/successes2.html !

I am not saying that the NK cell assays are inaccurate. The question is exactly what is being measured? I like the idea that there is something unusual about NK cells in ME but I am not sure what it is.

Prof. Edwards, respectively:

So you are saying that you are not sure what low NK Cell assays mean or indicate Because of our state of knowledge of NK cells?

also, You never attempted to answer this question.

1. Your statement implies that you don't see really much evidence for active infections to be significant in the determination of your patient set?

I actually think the things you are saying are quite enlightening, educating and rather exciting.

 

[Jonathan Edwards]

Would it have to be anti B-cell therapy? I've been thinking recently and read a little into anti-antibodies which have some potential. Being proteins, antibodies themselves have the potential to be bound to and have a highly specific region built into their structure. I realise we're a long way off being able to construct and manufacture such an antibody but it could theoretically work. The only problem I could thing of would be other things binding to it which could be problematic.

I suppose through anti-B cell therapies you're eliminating the cause of the problem but it does come with the obvious risks of immuno-suppression.

http://www.ncbi.nlm.nih.gov/pubmed/79255

The anti-antibodies in that paper were an unwanted response to giving anti-T cell antibodies. Anti-antibodies as therapy would be expected to be highly dangerous because of formation of immune complexes - effectively what used to be known as serum sickness that made horse anti-tetanus serum a dangerous treatment. Since plasma cells go on producing antibodies for months it would be hopeless to try to keep clearing them away I think. The paper you quote is in mice and you can do strange things to mouse tolerance with antibodies to T cells that as far as I know do not translate to humans.

 

[Jonathan Edwards]

Prof. Edwards, respectively:

So you are saying that you are not sure what low NK Cell assays mean or indicate Because of our state of knowledge of NK cells?

also, You never attempted to answer this question.

1. Your statement implies that you don't see really much evidence for active infections to be significant in the determination of your patient set?

I actually think the things you are saying are quite enlightening, educating and rather exciting.

The problem with NK cells as I see it is that each persons NK cells uses different inhibitory receptors and each person also has different proteins to bind these receptors. So an assay of NK function on K562 cells may be a bit misleading. If kingfishers are good at catching fish and owls are good at catching mice you may run into trouble if you test for killing efficiency with just fish (or mice) as bait. If there is a consistent difference in results of NK assays, and that is not the view of all researchers in the field, it may be telling us that ME patients' NK cells kill by a different route rather than kill less. If their NK cells were truly defective then that would either have to be genetic or secondary to something like autoantibodies. If genetic their relatives should suffer more infections and I doubt there is evidence for that being a significant problem. If the genetics are complex then the effect in relatives may be small but I think there ought to be some clues.

I don't want to exclude any possibilities but the calim that NK function is poor in vivo in ME seems to me to need further evidence.

I think I did say that I am not aware of consistent evidence for more active infections in ME. I do not personally have a patient set. I am going by the literature.